eMedicine Specialties > Nephrology > Drug- and Nephrotoxin-Associated Kidney Disorders

Nephritis, Radiation

Author: Eric P Cohen, MD, Professor of Medicine, Nephrology Fellowship Program Director, Department of Medicine, Division of Nephrology, Medical College of Wisconsin; Medical Director, Inpatient Dialysis Unit, Froedtert Hospital
Contributor Information and Disclosures

Updated: Jul 22, 2008

Introduction

Background

Radiation nephritis is kidney injury and impairment of function caused by ionizing radiation. It may occur after irradiation of one or both kidneys, and it may result in kidney failure.

Classic radiation nephritis occurs after bilateral local kidney irradiation. It is a syndrome of chronic renal failure occurring months or years after renal irradiation.¹ Acute radiation nephritis develops 6-12 months after irradiation, whereas chronic radiation nephritis develops years later. Radiation nephritis has also been discovered to cause chronic renal failure after bone marrow transplantation (BMT).² In addition, the use of yttrium–90–tagged (⁹⁰ Y-tagged) somatostatin and other radionuclides for radionuclide therapy cause radiation nephritis when they are filtered by the kidneys and reabsorbed by the renal tubule epithelium or when blood-borne exposure to the kidney cells occurs.³

The term nephritis was commonly used in the past; however, because radiation nephropathy is not an inflammatory condition, the term nephropathy is probably more appropriate. For older reports, the term nephritis will be used.

Pathophysiology

Radiation nephritis is due to cellular injury caused by ionizing radiation. All components of the kidney are affected, including the glomeruli, blood vessels, tubular epithelium, and interstitium.⁴

In the case of local kidney irradiation or total-body irradiation, the injury is direct. In the case of injury by radionuclide therapy, a radioactive substance can injure the kidneys if its pharmacokinetics cause it to lodge in the kidney during a time when it is still a radioemitter. This is the case for the⁹⁰ Y-tagged somatostatin, which has been used for treatment of neuroendocrine malignancies, and also for holmium-166–tagged (¹⁶⁶ Ho-tagged) phosphonate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP).^5,6

Oxidative injury to the DNA initiates injury to healthy tissue by ionizing radiation. This is a genotoxic injury. A cell with sufficient DNA injury eventually dies after several divisions. The delay in cell death may partially explain why radiation injury to healthy tissue is a delayed reaction.

The detailed mechanism whereby the kidney cells and tissues malfunction after this injury remains poorly understood. In experimental models, ultrastructural damage to the glomerular endothelium is observed 3 weeks after a 10-Gy (1000-rad) dose of local kidney irradiation and neutrophil adherence to the endothelium occurs.⁴ By 6-10 weeks after the same dose, a wave of tubular epithelial cell death occurs. This is followed by interstitial scarring. The scarring tends to be most severe in the outer cortex, and it proceeds inward. The progression of these events is accelerated with higher doses of radiation.

The earliest functional evidence of experimental radiation nephropathy is proteinuria, which is evident by 6 weeks in a radiation nephritis model with 17-Gy multifraction total-body irradiation. Azotemia and hypertension both are present by 12-15 weeks in the same model. The origin of the hypertension probably is similar to that of most experimental hypertension, though pressure-natriuresis curves have not been studied. Renin levels in systemic blood are normal or low, and blood and intrarenal angiotensin II levels are within the reference range (ie, not elevated).

In clinical experience, radiation nephritis does not occur until months after the kidneys are exposed to sufficient ionizing radiation. Early data suggested that a dose of 20 Gy (2000 rads) given in multiple fractions over several weeks can cause radiation nephritis.¹

Radiation nephritis after BMT (BMT nephropathy) occurs after a lower dose of irradiation than what was traditionally accepted. This dose is given over days, not weeks, to the whole body (total-body irradiation) and is accompanied by chemotherapy, which may account for the unexpectedly dramatic effect on the kidneys. Proteinuria is usual, though generally not in the nephrotic range. Azotemia and hypertension also develop. Anemia out of proportion to the degree of azotemia is a characteristic finding. Severe cases may be associated with a hemolytic- or uremic-like picture, with thrombocytopenia, microangiopathic hemolytic anemia, and a high blood level of lactate dehydrogenase (LDH). This last syndrome may be the result of severe endothelial injury.

In the case of unilateral renal irradiation, progressive scarring of the irradiated kidney may occur, with severe hypertension related to renin release by the single irradiated kidney.

Frequency

United States

Radiation nephritis does not occur in all irradiated patients. In the large British series of classic radiation nephritis described by Luxton, only 20% of subjects developed radiation nephritis, though each received more than 2500 rads to the kidneys.¹

The form of radiation nephritis in patients who receive BMT occurs in 10-20% of these patients.

In a report from Seattle, Wash, 30 of 83 subjects treated with¹⁶⁶ Ho to DOTMP developed some kidney injury; 7 subjects had thrombotic microangiopathy (ie, hemolytic uremic syndrome).⁶

International

No international variability is apparent in radiation nephritis, except as determined by the use of therapeutic irradiation.

Mortality/Morbidity

As with other causes of chronic renal failure, radiation nephritis may be asymptomatic. When it sufficiently reduces kidney function, symptoms and signs of renal failure occur. End-stage renal disease and the need for dialysis or transplantation may develop. In patients with BMT nephropathy who are receiving dialysis, the survival rate is less than that of age-matched control subjects.⁷

• Proteinuria occurs, but it is usually not a striking feature in patients with radiation nephritis. Reports of classic radiation nephritis generally describe non–nephrotic-range proteinuria (<3 g/d). In BMT nephropathy, the average urinary protein level has been reported at 2.5 g/d.
• Hypertension is a typical feature. In classic radiation nephritis, malignant hypertension may affect as many as 30% of patients and can occur as late as 11 years after irradiation. In BMT nephropathy, hypertension is a cardinal feature and observed along with azotemia. Were it not for antihypertensive agents, malignant hypertension would probably be a major feature of BMT nephropathy.
• On hematologic analysis, accompanying anemia is present in both radiation nephritis and BMT nephropathy and is more severe than that expected for the degree of azotemia. In severe cases of BMT nephropathy, hemolytic anemia, a high blood LDH level, and a decreased platelet count may be present. This syndrome may be mistaken for hemolytic-uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP).

Race

No data on the racial variance of radiation nephritis have been published.

Sex

No confirmed sex-based differences in radiation nephritis have been reported. At the BMT unit of the Medical College of Wisconsin, BMT nephropathy has affected more women than men, but other centers have not had this experience.

Age

No age-based differences in susceptibility to classic radiation nephritis have been confirmed. However, in the case of BMT nephropathy, children appear to be more likely to develop this syndrome than adults.

Clinical

History

• Previous exposure to a sufficient dose of ionizing radiation is a necessary element in the patient's history. External-beam irradiation is usually a clear-cut feature in the history, and it should have encompassed the kidney areas. Use of a radioactive isotope, in therapeutic doses, may not be obvious.
• Classic radiation nephritis requires exposure of the kidneys to x-rays or gamma rays in a dose higher than 2000 cGy (rads). However, radiation nephritis does not always ensue after the kidneys are irradiated.
• Newer x-ray therapies are sharply focused on the area to be treated; therefore, it is very unlikely that the kidneys would be irradiated in a case of uterine cervical irradiation, for instance.
• In patients who have undergone BMT, a history of total-body irradiation for pre-BMT conditioning should be determined. Partial renal shielding reduces but does not eliminate the risk of BMT nephropathy.
• Because radiation nephritis is a delayed injury, renal disease that quickly follows kidney irradiation (ie, within hours or days) is usually caused by some other factor.
  • Classic acute radiation nephritis occurs 6-12 months after irradiation, and chronic radiation nephritis may not develop for years.
  • Similarly, proteinuria or hypertension ascribed to radiation nephritis does not develop for months or years.
• Expected symptoms of radiation nephritis and BMT nephropathy are the same as those observed in patients with chronic renal disease.
  • Nocturia may develop due to the loss of urine concentrating ability.
  • Retention of salt and water may lead to edema and an increase in blood pressure.
  • Anemia may occur, with fatigue, dyspnea, and loss of endurance.
  • Loss of appetite, nausea, and weight loss may occur when there is a severe reduction in renal function.
  • Itching may occur with advanced renal failure, that is, stage V chronic kidney disease (see Staging).

Physical

• Hypertension, often severe, is a major feature of radiation nephritis. It may be the only clinical feature.
• Blood pressure elevation can be significant. When this elevation is associated with end-organ damage, such as eyeground changes or encephalopathy, it is termed malignant. Malignant hypertension has been reported in radiation nephropathy. Eyeground abnormalities, such as cotton-wool spots, retinal hemorrhage, and even optic disc edema, may occur at levels of blood pressure elevation that ordinarily would not cause such eyeground changes.⁸
• Long-standing hypertension may result in left ventricular enlargement or hypertrophy, which may be detectable on examination. Findings on physical examination are not specific for radiation nephritis or BMT nephropathy.

Causes

• The essential component for causing radiation nephritis is sufficient exposure of the kidneys to ionizing radiation.
• BMT nephropathy is also caused by irradiation, though histologic changes, similar to those of BMT nephropathy, were described in a single patient who had undergone BMT and who had chemotherapy-based pre-BMT conditioning without irradiation.
• Not all patients exposed to sufficient renal irradiation develop renal injury. The reason for this clinical variability is unknown.
• The heterogeneity of response of healthy tissue to ionizing radiation is poorly understood. No reliable clinical predictors are available for the development of radiation nephritis. Some individuals may develop radiation nephritis at a dose of radiation that has no clinical effect on others.

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